Compressed tablets containing compacted starch as binder-disintegrant ingredient

ABSTRACT

A directly compressed tablet containing as a binder-disintegrant ingredient, a partially cold-water soluble, cold-water swelling starch material derived from compacted granular starch, e.g. compacted native corn starch. The compacted granular starch is a superficially dry, free-flowing powder in which the starch is in the form of a mixture of birefringent granules and nonbirefringent fragments of granules, in which some aggregates of granules and fragments are present. The use of the starch binder-disintegrant ingredient allows active ingredients, e.g. pharmaceuticals, to be tabletted by direct compression.

[21] Appl. No.

United States Patent Rolland W. P. Short;

Frank Verbanac, both of Decatur, Ill. 839,590

July 7, 1969 Nov. 23, 1971 A. E. Staley Manufacturing Company Decatur,lll.

Continuation-impart of application Ser. No. 646,496, June 16, 1967, nowabandoned. This application July 7, 1969, Ser. No. 839,590

[ 72] Inventors [22] Filed [45] Patented [73] Assignee {54] ,,COMPRESSEDTABLETSCONTAINING COMPACTED STARCH AS BINDER- DISINTEGRANT INGREDIENT 8Claims, 4 Drawing Figs.

52 U.S. c1. 424/361, 106/210, 424/229, 424/230, 424/280, 424/300, 424324, 252/1;99, 71/77, 99 140, 8/79, 264/1 18,

, 127/32 [51] Int. Cl A61] 3/10 [50] Field of Search 424/361;

[56] References Cited UNITED STATES PATENTS 3,034,911 5/1962 McKee et a1106/210 3,101,299 8/1963 Ferrand 424/361 X 3,424,842 1/1969 Nurnberg424/94 3,453,368 7/1969 Magid 424/280 3,490,742 1/1970 Nichols et al.252/99 Primary Examiner-Shep K. Rose Attorney-Charles J. NeyersonABSTRACT: A directly compressed tablet containing as abinder-disintegrant ingredient, a partially cold-wa ter soluble,

COMPRESSED TABLETS CONTAINING COMPACTED STARCI-I AS BINDER-DISINTEGRANTINGREDIENT CROSS-REFERENCE This application is a continuation-in-part ofapplication Ser. No. 646,496, filed June 16, 1967 now abandoned.

DISCLOSURE OF THE INVENTION This invention relates to the manufacture ofcompressed tablets and more particularly to compressed tablets whichcontain a starch binder-disintegrant ingredient in the form of adirectly compressible compacted starch powder which permi the tablets tobe made by the direct compression technique.

.Of the multitude of forms in which pharmaceutical products may bedispensed, the compressed tablet form is, by far, that most frequentlyemployed today. Ease of packaging and handling, and, most importantaccuracy of dosage in administration are among the advantages stemmingfrom the use of medicament-containing tablets. For essentially the samereasons, the compressed tablet also plays an important role in otherfields as a dispensing unit. Examples of nonpharmaceutical materialsmarketed in compressed tablet form include such diverse materials aslaundry detergents, confections, artificial sweeteners, fish foods,plant growth regulators, pesticides, herbicides, and dyes. While theactual characteristics of various tablets differ depending on theparticular nature and planned use of the several tablets, the generallymore important characteristics fall into three areas of consideration.

Since most tablets are designed for use in accurately dispensing anactive material into a fluid medium, an evaluation of the tabletincludes a consideration of the tablet disin tegration properties in thefluid medium. While some tablets such as those designed for use as athroat lozenge desirably are slowly disintegrative in the fluid mediumin which they are placed for use, in most cases rapid disintegration ofthe tablet is desired. For example, a tablet embodying an ingestibleanalgesic, such as aspirin, should rapidly break down in the digestivefluid of the stomach to make the active ingredient promptly available tothe organism. The present invention is particularly concerned with suchtablets of relatively rapid disintegration capability.

The second and third important tablet characteristics, friability andhardness, are somewhat related in that as tablet hardness increases thefriability of the tablet generally decreases. Excessive friability isundesirable since dusting and crumbling of the tablet results in atleast some diminution in active ingredient dosage, detracts from thetablet appearance and consumer appeal, and reduces the effectiveness ofany tablet markings. insufficiently hard tablets, in addition toexhibiting the efl'ects of excessive friability, are prone to breakageand chipping, particularly in transport where they may be subjected torepeated mechanical shock.

Accordingly, for most purposes, and particularly for pharmaceuticalapplication, a hard, nonfriable tablet possessing acceptabledisintegration characteristics is the goal of the tablet manufacturer.Other properties are, of course, important such as color stability andnonhygroscopicity but the desideratum remains the production of a tabletof the type described.

Certain materials such as sodium chloride, paradichlorobenzene,hexamethylenetetramine, and certain medicaments are readily directlycompressed alone in dry form into a firm, coherent mass in a tabletmachine. However, the majority of active ingredients in order to betabletted require a binding agent to be added. The tablettedformulations generally also contain additional ingredients, such aslubricants, disintegrants, fillers, colorants, and the like. The termsbinding agent," binder," and filler" are self-explanatory. Adisintegrant is an agent which is effective, when the tablet is placedin the proper fluid environment, to promote destruction of the tablet'sphysical integrity. A typical disintegrant employed in tabletting isgranular starch.

A given material may perform more than one of the single functions ofbinding, filling, and promoting disintegration. The principal component,other than the active ingredient, that is employed to provide theimproved compressed tablets of the present invention is such adual-functioning material and is referred to herein as abinder-disintegrant.

In general, three methods are known for the preparation of mixturessuitable to be employed in a tablet-making machine. In two of themethods commonly used for the preparation of tabletting machine feedmaterial, the goal in each is the preparation of the feed material inthe form of free-flowing granules. One technique involves a dry, and theother a wet, method of granulation. Dry granulation is also referred toas slugging or double compression. In accordance with the sluggingtechnique, thejnitially prepared.pulverulentadmixture of activeingredient, filler, binder and the like is formed into large tablets orslugs by dry compression molding. These slugs are then milled togranules of predetermined size adapted to be used as the feed to thetablet-making machine. This method is expensive, requiring considerableequipment, labor, and power. The technique, moreover, does not alwaysprovide suitable tablets.

The wet granulation technique involves adding a moistening agent such aswater or ethylene glycol to the tabletting in gredient mixture toprepare a moistened mass, oven drying the wetted mass, and milling thedried mass into granules adapted to be used in the tabletting machine.The wet granulation method likewise is undesirably time consuming andexpensive. This method, moreover, has the limitation of not being usefulwhen the tablet ingredients are incompatible to wetting or are heatsensitive.

The third and simplest procedure employed in preparing tablettingformulations involves intimately and uniformly dry blending theingredients employed, e.g. active ingredient, binder, filler,disintegrant, and lubricants, to provide a pulverulent mixturedisplaying the requisite flowability for adequate feeding to the tabletmachine. Since in this method the granulation step is eliminated, theformulations are said to be directly compressible" into tablets, and thetablet-forming operation is referred to as direct-compression"tabletting. This procedure, by virtue of its simplicity, obviously ispreferred for use. Using ingredients heretofore available, however, theingredient mixtures obtained by mere dry mixing generally do not exhibitadequate flowability and are not adapted to be fed directly to thetabletting machine to prepare tablets of uniform and acceptableproperties. The limited acceptance of preparing compressed tablets bydirect compression has stemmed principally from the unavailability ofsuitable and inexpensive direct compression binding agents. Of thosematerials which do qualify by reason of their binding properties,moreover, few are characterized by satisfactory overall properties. Forexample, the most widely used material at present for binding tablets bythe direct compression method, spray-dried lactose, is unacceptable inmany uses because of its marked tendency to turn brown on aging. Thegreat percentage of tabletting operations, therefore, have been forcedto resort to other fonnulation techniques such as the wet and drygranulation methods, and the art has continued to search for an improvedmaterial capable of being employed as a binder in the preparation oftablets by direct compression which are rapidly disintegrative,resistant to breakage and crumbling, and otherwise satisfactory.

Accordingly, it is an object of the present invention to provide animproved binder for the manufacture of compressed tablets. It is anotherobject of the invention to provide such an improved binder havingcharacteristics that permit it to function also as a disintegrant. it isan additional object of the invention to provide active ingredient,binder ingredient formulations directly compressible into tablets. It isyet a further object of the invention to provide a compressed tabletcontaining a binder-disintegrant ingredient, the tablet being hard,nonfriable, and readily disintegrative in an aqueous medium. Yet anotherobject of the invention is to provide a method for preparing compressedtablets. A particular object of the present invention is to provide ameans whereby tablets of ex cellent properties can be prepared by directcompression. The means of attaining these and related objects will beevident from the following description and examples.

For a more complete understanding of the nature and scope of theinvention reference may now be had to the following detailed descriptionthereof with illustrative working examples, and to the accompanyingdrawings, wherein:

FIG. 1 is a photomicrograph, taken under bright field illumination ofordinary corn starch at a magnification of 425;

FIG. 2 is a photomicrograph corresponding to FIG. 1 but with the lightpolarized;

r it]. 3 is a photomicrograph, taken under bright field illumination ofcompacted corn starch, useful in accordance with the present invention,at a magnification of 425; and

FIG. 4 is a photomicrograph corresponding to FIG. 3 but with the lightpolarized.

Compacted starches constitute a known class of materials. They areprepared by subjecting a granular starch raw material to pressure in thepresence of water to effect distortion and fracture of at least some ofthe granules and produce adhesion between particles of the resultantmass. The resultant compacted material may have differing cold-waterswelling properties and contain varying amounts of cold-water solublematerial depending primarily upon the particular pressure, temperature,and moisture conditions utilized. Specific techniques commonly employedinclude passing the starting starch through the nip of rotating rollsoperating at the same or different speeds, as described in US. Pat. Nos.2,098,293; 2,168,524; 2,464,081; and 3,196,044, and working the starchin the course of an extrusion operation as shown in US. Pat. Nos.3,137,592 and 3,159,505. Compacted starches heretofore have foundutility primarily as dustless carbohydrate nutrients in the brewingindustry and as binders in the preparation of rough-molded productscontaining relatively coarse aggregate materials such as foundry coresand charcoal briquettes.

It now surprisingly has been discovered that certain compacted starchpowers, described more fully hereinafter, advantageously arecharacterized by properties which enable them to be dry mixed withactive ingredients and conventional tabletting aids, such as fillers,lubricants, and the like, to prepare active ingredient-containingformulations which are directly compressible into tablets inconventional tabletting equipment. The present invention thereforeprovides a highly valuable means whereby tabletting operations may begreatly simplified, and the troublesome and time-consuming preliminarygranulation and slugging steps which characterized most tablettingoperations heretofore available may be eliminated. The compacted starchpowders employed in the present invention, moreover, advantageously arecharacterized by properties which satisfy both the requirements of abinder for the active ingredient and a disintegrant for the tablet inaqueous media. Consequently, suitable direct compression tablets ofsatisfactory hardness, friability, and disintegration propertiesadvantageously may be prepared by means of the present invention usingthe compacted starch powders as a sole, dualfunctioningbinder-disintegrant, and the heretofore commonly required practice ofadding separate ingredients as the binder and disintegrant with theattendant problems of properly mixing multiple ingredients and balancingdosage levels no longer need be followed. The starch binder-disintegrantingredient employed in preparing direct compression tabets in accordancewith the present invention, furthermore, easily and cheaply may beobtained from readily available and inexpensive starting raw materials,namely granular starches. Of such binder-disintegrant compacted starchesmany embodiments are characterized by low color, color stability, andacceptability for human consumption. The present invention, therefore,includes what may be said to be a universal" ingredient for directcompression tabletting, whereby a wide range of active ingredients,including many pharmaceuticals tabletted heretofore only with greatdifficulty, if at all, now easily and inexpensively may besatisfactorilytabletted by direct compression.

The compacted starch powders employed in the practice of the presentinvention are derived from appropriately compacted granular starch rawmaterials and are superficially dry, free flowing, partially cold-watersoluble materials which swell in cold water and have a relatively highloose bulk density. The powders themselves are directly compressible inconventional tabletting equipment into relatively rapidly disintegrativeplacebo tablets of high hardness and low friability. Microscopicexamination of the compacted starch powders reveals the starch contentof the materials to be in the form of a mixture of birefringent granulesand nonbirefringent fragments of granules, in which some aggregates ofgranules and fragments are present. These characteristics of thecompacted starch powders on microscopic examination are apparent fromthe photomicrographs reproduced in FIGS. 1-4. In FIG. 1 granules ofordinary corn starch are shown as viewed with unpolarized light at 425magnification. FIG. 2 shows the same granules viewed with the lightpolarized at the same magnification. It will be noted that in FIG. 2 thegranules all exhibit birefringence (i.e. the crosses) which ischaracteristic of starch granules.

In FIG. 3 a sample of compacted starch powder, which is directlycompressible into tablets in accordance with this invention, is shown asviewed with unpolarized light at 425 magnification. A number of starchgranules appear in F IGv 3 along with aggregates and granular fragments.When the same sample of compacted starch powder is viewed underpolarized light at the same magnification, it is clearly seen that thesample is a mixture of birefringent granules and nonbirefringentfragments of granules, in which there are aggregates of granules andfragments.

Compacted starch powders of the invention have the followingcharacteristics:

As used herein, the term superficially dry is intended to indicate apowder is dry in the visual and tactile sense. A placebo tablet is atablet prepared by directly compressing one material alone such as acompacted starch powder. The terms cold-water solubility, swellingpower, hardness," friability," disintegration time, and granular starchraw material are defined as follows:

Cold-water solubility-The percent by weight of the starch dry substancewhich dissolves in water at 25 C. when determined by the followingprocedure: One gram of the starch product being. tested is added to ml.of water at 25 C. in a high-shear blender and mixing is carried out at1,500 r.p.m. for 2 minutes. The resultant sample is then transferred toa 250 ml. round-bottom centrifuge tube and centrifuged for 15 minutes at2,000 r.p.m. A 25 ml. aliquot of the clear centrifugate is transferredto a tared aluminum pan and evaporated to dryness on a steam bath. Thedish is then dried to a constant weight at 1 10 C. The weight of thedried material in the pan multiplied by 400 and divided by the drysubstance weight of the original sample is the cold-water solubility ofthe starch material. By this test commonly available granular starchesare essentially cold-water insoluble, generally containing less thanabout 2 percent by weight cold-water solubles and in the case ofunmodified starches less than about 1 percent.

Swelling power-a measure of the ability of a starch to swell in coldwater as determined by method 56-20 of Cereal Laboratory Methods"published by the American Association of Cereal Chemists. For referencepurposes, uncompacted granular starches generally have a swelling poweron the order of about 2.

Hardnessa measure of the strength of tablets (average of or moretablets) and their ability to retain their physical integrity, expressedin terms of kilograms, as determined by the conventional procedure usinga model B tablet hardness tester of the Strong-Cobb-Amer Company,Cleveland, Ohio, to obtain an indicated pressure gauge reading atfracture of the tablet (tablet mounted on edge in tester) andmultiplying the indiczwu hardness value by a factor of 0.78 to convertthe gauge reading to actual pressure. For example, a satisfactory activeingredient-containing tablet generally should have a hardness in thistest of at least about 4 kg.

Friability-a measure of the tendency of tablets (average of 10 or moretablets) to crumble and dust, expressed in terms of percent weight loss,as determined by the Roche" test described in the Journal of theAmerican Pharmaceutical Association, Scientific Edition, Vol. 45 pages114-1 16 (1956). For reference purposes, an active ingredient-containingtablet displaying a weight loss of less than about 1.0 percent generallyis considered to have acceptable friability.

Disintegration time-the time observed for tablets (range of six tablets)to disintegrate in water as determined by a modification, in which theuse of discs is eliminated, of the procedure for uncoated tabletsdescribed in Pharmacopeia of the United States of America, 16th Edition,934-936 (1960).

Granular starch raw material-the starting starch which has beencompacted in the preparation of the compacted starch powders of theinvention. The starting starch suitably may be any granular starchderived from the root, stem, or fruit of a plant. Specific examples ofstarch-yielding sources include com, rice, wheat, potato, tapioca, andarrowroot. The starting starch raw material suitably may be unmodified,modified, derivatized, or cross-linked. Examples of unmodified starchesare the granular starches conventionally prepared from natural starchsources by removal of fiber, gluten, and other proteinaceous impurities,with or without subsequent washing, drying, screening, bleaching, and/orsterilization. Modified granular starches include thin-boiling starchesmade by heating a water slurry of an unmodified starch below thegelatinization temperature with a mineral acid (e.g. hydrochloric acid)or an oxidizing agent (e.g. alkaline hypochlorite). Derivatized granularstarches include starch esters, e.g. starch acetate and starchpropionate, and starch ethers, e.g. hydroxyethyl, carboxymethyl, andcyanoethyl starch, prepared from unmodified or modified granularstarches with retention of the granular structure. Granular cross-linkedstarches include ungelatinized starch products made by reacting anunmodified, modified, or derivatized granular starch with apolyfunctional reactant, e.g. phosphorous oxychloride orepichlorohydrin.

The freeflowing property of the compacted starch powders employed in theinvention is exemplified by the ability of the powders to meet thefollowing arbitrary test: a sample of powder being tested is poured intoa 24/40 standard taper glass powder funnel, the tip of which issuspended normal to, and one inch above, a horizontal, dry, smooth papersurface. Powder is poured through the funnel until the cone of powderformed on the paper surface below reaches the tip of the funnel, and thefunnel plugs. The average radius of the cone base is determined bytaking four radius measurements from the funnel tip along diametersintersecting at right angles and averaging the values. From the coneheight (1 inch) and the average radius of its base, the angle formed bythe inclined surface of the powder cone and the horizontal, hereinreferred to as the angle of repose," can be determined using wellknowntrigonometric principles, i.e. by calculating the tangent of the angleof repose. A powder which is not free-flowing in the sense of the termas employed herein displays an angle of repose in this test of more thanabout 40 The more preferred free-flowing characteristics are displayedby compacted starch powders forming an angle of repose in the range offrom about 20 to about 35.

Due to the availability and low cost of the starting raw materialrequired, compacted starch powders derived from corn starch, and morepreferably an unmodified corn starch, constitute the binder-disintegrantingredients preferred for utilization in the present invention. Suchstarch raw materials, moreover, provide resultant binder-disintegrantingredients which display excellent color stability during storage andin the ultimate tablet. By reason of the excellent overall properties oftablets which can be obtained by the use thereof, the particularlypreferred binder-disintegrant ingredients are superficially dry,free-flowing powders of the above-described type characterized by acold-water solubility of from about 6 to about 15 percent and a swellingpower of from about 5 to about 8 and being derivatives of a bleachednative corn starch, e.g. hypochlorite-bleached native corn starch.

The starch binder-disintegrant ingredients employed in the presentinvention are prepared from the starting granular starch raw materialsby the same basic steps heretofore utilized in preparing powders ofcompacted starches and in general involving compacting the startingstarch raw materials in the presence of water, comminuting the resultantcompacted material, and classifying the comminuted intermediate into thedesired particle size fraction.

The compaction step suitably may be carried out in any convenient deviceconventionally employed for this purpose. As described above, the morecommonly used devices include differential roll mills, concurrent rollmills, extruders, and the like. The moisture content of the granularfeed starch and the temperature which the starch attains during thecompaction are important variables in achieving a suitably modifiedcompact. In preparing compacted starches suitable for use in the presentmethod, temperatures should be limited to those below the gelatinizationtemperature of the particular starch used. Higher temperatures providecompacts which, when comminuted, yield powders which are overgelatinizedand have poor disintegrant properties. Optimum compaction conditionsgenerally include temperatures in the range of from about 20 to about 50C.

The water content of the granular starch feed must be in the rangewhereby the properties of the granular starch feed are altered to thedesired degree in the compaction treatment. For a given starch and agiven compaction device, limits for the moisture content will exist atwhich the starch feed is either too dry or too wet for the compaction tosufficiently change the properties of the starting starch. For a givenstarch and compacting device, however, the operable and optimum watercontent ranges easily may be determined in the manner known anddescribed hereafter, i.e., varying the feed starch moisture content andnoting the degree of starch modification achieved in terms of the effecton the cold-water solubility and swelling power of the starch. As ageneral rule, in most conventional starch compaction equipment, watercontent in the feed granular starch in the range of from about 20 toabout 50 per cent of the starch total weight is used to achieve thedesired amount of compaction. The lower moisture levels in this range,e.g. from about 20 to about 30 percent, are generally more adapted foruse in roll-type compaction equipment such as differential roll mills,and the higher water contents in this range, e.g. from about 30 to about50 percent, are better adapted for use in devices effecting the desiredworking in a confined space such as in a screw-containing barrel-typeextruder. Since commonly available granular starches generally have amoisture content on the order of 10-12 percent, water usually must beadded to the granular feed starch prior to compaction.

While, as stated above, the particular compaction technique employed inpreparing the starches employed as binder-disintegrants in the presentinvention is not critical, a compaction method which is particularlyuseful is exemplified by that disclosed in US. Pat. No. 2,464,081entailing the use of a differential mill. In a typical application ofthis technique, a granular starch feed having an adjusted moisturecontent in the range of from about 24 to about 32 percent by weight isfed through the mill operated with a gap between the rolls in the rangeof 3 to 12 mils. Typical roll speeds vary between 35 to about 70 feet(linear) per minute using a speed differential of from about 10 to about20 feet per minute. Roll temperatures maintained by circulating waterthrough the rolls generally vary between about 10 to about 40 C. Morethan one pass through the rolls generally is required to sufficientlymodify the starting starch properties with up to four passes beingcommon.

Another particularly useful compaction technique utilizes a rotatingpellet mill which is adapted to subject the starch feed to thesufficient amount of working during the formation of pellets therefrom.An example of a typical pelletting operation which achieves suitablecompaction generally employs a pellet mill having dies 3/16 inch indiameter and 1% inches in length in which the starting granular starchat a moisture content of from about 20 to about 30 percent by weight ispelletized at a feed rate of 900 to 1,000 lbs. per hour with the millrotating at 125-150 r.p.m. Advantages of utilizing a pellet mill arethat one pass through the mill usually is sufficient to provide thedesired starch modification and that a significantly reduced amount offines is produced as compared to most other compaction techniques.

The material produced by the required amount of compaction then isground and screened to a suitable particle size, the moisture contentbeing adjusted during the recovery of the desired powder from thecompact. For optimum results, the compact is dried prior to beingground. Drying lessens the proportion of fines produced in the grindingstep and guards against possible further undesirable starch alterationduring grinding. in the drying, the moisture content of the compactedmaterial is commonly reduced to from about 4 to about l4 percent byweight.

The grinding suitably may be carried out in any grinder, mill orcombination of comminuting devices adapted to reduce the compact to afree-flowing, directly compressible powder. It

has been found that the more suitable tablet binder-disintegrant powdersare those which are relatively fine. ln the grinding step, therefore,the compacted starch generally is reduced to a powder of which at leastabout 30 percent of the total weight thereof is material of 270 mesh.The term mesh, as used herein, refers to the U.S. Standard Sieve Series,A.S.T.M. specifications. The presence of too great a proportion of finesis not conducive to optimum tabletting so it generally is preferred tocontrol grinding to provide a powder containing less than about 90percent by weight material of 270 mesh. The more preferred powdersobtained in the grinding step, by virtue of the properties of thetablets obtained therefrom and their adaptability to tabletting machineoperation, are those ground to from about 45 to about 75 percent byweight material of 270 mesh. A specific grinding technique suitable foruse involves initially grinding the compact to l mesh and thencompleting grinding in a mill adapted to recycle all +100 mesh material.

The water content of the compacted starch powder has an effect on thebinder-disintegrant properties of the material. Too low or too high awater content detracts from the properties of the ultimate tabletsformed. Generally moisture contents in the range of from 9 to about 16percent of the powder total weight are suitable with the more preferredresults usually being obtained at moisture contents in the range of fromabout ll to about 13 percent by weight. Accordingly, following grinding,the moisture content of resultant powder preferably is adjusted, ifnecessary, by drying or the addition of water.

As stated, the binder-disintegrant starch powders preferred for usecontain a low proportion of coarse particles. Generally, it is desiredthat the powder contains less than about percent by weight material of+80 mesh. The more preferred powders are essentially free of +40 meshmaterial Proportion of Powder,

Particle Size total weight 40-80 mesh 5 -200 mesh 5-30 200-270 meshl0-40 through 270 mesh 45-75 At least 10 percent should be between 80and 270 mesh to help in imparting free-flowing characteristics.

In the preferred preparation of tablets by the present invention, anactive material ingredient is thoroughly mixed by any suitable dryblending technique with one or more of the above-described compactedstarch powders in 7 relative amounts required to provide a resultantsuperficially dry, freeflowing formulation directly compressible intotablets, and the fonnulation then is tabletted by direct compression.

Active ingredients contemplated to be employed in the preparation oftablets by the present invention constitute all active ingredientscompatible with the above-described compacted starch powders informulations directly compressible into tablets. The present inventionis particularly adapted for use in preparing tablets containingpulverulent pharmaceuti cally active materials. Specific examples ofpharmaceutically active ingredients which advantageously may betabletted by the present invention include ascorbic acid, sodiumpaminosalicylate, phenacetin, and N-acetyl-p-aminophenol, all materialswhich heretofore generally have been tabletted only with greatdifficulty. The particular nature of the active material is notcritical, however, and nonpharmaceutical active materials, e.g.pulverulent detergents, dyes, pesticides, and foods, forming directlycompressible mixtures with the compacted starch powders can also beemployed.

The amount of active material ingredient employed in preparing tabletsaccording to the present technique depends, inter alia, upon the natureand relative compatibility of the active material, and the end use forwhich the tablet is desired, the latter dictating thereby the tolerableproperties in terms of hardness, friability, and/or disintegratabilityof the final tablet. Given the minimum and preferred characteristicsdesired in the final tablet, the tolerable limits on the weight ratio ofactive ingredient to binder-disintegrant for a particular activeingredient easily may be determined by the known technique ofsequentially increasing the active ingredient content of the tablet. Ingeneral, acceptable active material-containing tablets are those whichdisplay a hardness of at least about 4 kg., preferably above about 5kg., and a friability corresponding to a weight loss of less than aboutl.0 percent, preferably less than about 0.5 percent. For a tablet havingsuitable friability, a lower hardness generally can be tolerated.

Depending upon the type and contemplated use of the final tablet, thedisintegration requirements may vary over a wide range. A particularfeature of the present invention is that a wide range of activeingredients may be tabletted to provide tablets displayingdisintegration times in aqueous media of generally less than 30 minutesand more usually less than 15 minutes and in the range of from about 0.5to about l0 minutes. The rapid disintegration rates of tablets preparedby the present method, as stated, stem from the advantageouscharacteristics of the compacted starch powders to function not only asexcellent binding agents but as agents which accelerate tabletdisintegration as well. ln general, specific embodiments of tabletsprepared in the invention contain from about 5 to about 90 percent byweight active ingredient, dry substance basis. An additional feature ofthe present invention is that, by the use of the binder-disintegrantcompacted starch powders, even many pulverulent active ingredients whichthemselves are noncompressible or only poorly compressible, exemplifiedby the pharmaceuticals named, may be formed into suitable tabletscontaining from about 20 to about 50 percent and above of the activeingredient based on the tablet dry substance weight.

Adjuvants, such as tabletting lubricants, fillers, antisticking agents,coloring agents, and the like, conventionally employed in preparingparticular tablets by direct compression, suitably may be incorporatedin appropriately effective amounts into the compressible formationsformed in the present invention. A lubricant such as talc, magnesiumstearate, or stearic acid, when employed, generally is added in anamount ranging up to about percent by weight of the total tablettingformulation. Colloidal silica constitutes a typical antisticking agentor socalled glidant." A glidant such as colloidal silica, whenincorporated in a formulation, usually is added in an amount ranging upto about 2 percent of the formulation total weight. Fillers, which mayalso function as supplemental binders or disintegrants, where employed,must not be added in amounts which impair undesirably the directcompressibility of the tabletting formulations.

While the compacted starch powders employed in the present invention arecapable of satisfying the dual requirements of a binder-disintegrant,the present invention, as stated, also contemplates embodiments whereinefiective amounts of another direct compression binder such as lactoseand the like and/or a separate disintegrating agent such as nativecornstarch also is incorporated into the formulation. In most cases,however, the addition of such additional binders is unimportant in viewof the excellent characteristics of the binder-disintegrant compactedstarch powder of this invention. in view of this, it will be understoodthe present invention is directed primarily to embodiments wherein thesuperficially dry, free-flowing binder-disintegrant starch of thisinvention is the major binder ingredient employed, i.e. present in anamount corresponding to at least 50 percent of the total weight amountof tablet binding agent employed, and more preferably is the solebinding agent added to the formulation for this purpose. In someinstances, a supplemental disintegrant may provide some improvement. Anexample of this is in the preparation of tablets of sodiump-amino-salicylate dihydrate wherein the disintegration rate of thetablet advantageously may be further accelerated by the addition of aconventional granular starch disintegration aid.

The more desirable tablets are prepared from superficially dryformulations containing from about 5 to about percent moisture based onthe formulation total weight. Accordingly, appropriate adjustment of themoisture content may be made, where necessary or desirable, during theformulation operation to improve the tabletting characteristics of themixture. It may also be desirable, after mixing the ingredients, toscreen the formulation to remove any oversize particles introduced inthe active ingredient or tabletting aids and thereby to improvetabletting efficiency. In this respect, removal of +40 mesh particles byscreening generally is desirable.

in accordance with the present invention any conventional single orrotary tablet making apparatus suitably may be employed in thetabletting operation. As is standard in conventional tablettingpractice, optimum results are obtained for particular formulations bythe use of the highest pressure settings consistent with good tabletpress operation.

Tablets prepared from a given batch of tabletting formulation by meansof the present invention are essentially uniform in thickness, weight,and active ingredient dosage level and have excellent surface smoothnessas indicated by the lack of pits and cracks. A further characteristic ofthe tablets made according to the invention is that a substantialduplication of tablet properties is obtained by grinding the tablets toa freeflowing powder and retabletting.

While the above discussion has been limited to the preparation oftablets by direct compression, it further will be understood that thedescribed free-flowing, directly compressible active ingredient andcompacted starch powder-containing formulations, of course, also can beemployed in the preparation of compressed tablets either by the doublecompression technique wherein slugs initially are prepared from aformulation and the slugs subsequently dry granulated to prepare tabletmachine feed material or by the wet granulation method wherein a wettingagent, such as water, is added to a formulation, the moistened mass isdried without gelatinizing the compacted starch powderingredient, andthe resultant dried material is ground into granular feed for thetabletting machine. Compressed tablets which can be prepared by eithermethod have essentially the same characteristics as those produced bydirect compression. In view of the adaptability of the formulationsprepared hereby to direct compression tabletting, however, the dry andwet granulation methods are impractical and can be anticipated to berarely, if ever, employed.

The invention having been described in detail, the following examplesare presented to show specific embodiments thereof. It will beunderstood the examples are given for illustration purposes only and notby way of limitation.

EXAMPLE I This example illustrates the preparation of suitable tabletbinder-disintegrant starches from an unmodified cornstarch and the useof the binder-disintegrant starches in the preparation of tablets bydirect compression.

Three samples of ground hypochlorite-bleached native cornstarch (starchA) having the properties set forth in table 1 were converted tocompacted starch powders by three different techniques. The techniquesemployed were as follows: Technique 1 (Pelletizing) One sample of thehypochlorite-bleached native cornstarch was moistened to a water contentof 24-25 percent by weight and the moistened starch was pelletized at arate of about 960 pounds/hour on a California Process Series CM-F BMaster pellet mill having dies 3/16 inch in diameter and 1% inches inlength and operated at about 130 r.p.m. The resultant pellets /4 incheslength) were then dried in a rotary drier to 7.4 percent by weightmoisture. The dried pellets were then ground to -10 mesh in a Model DS-6Series [606 stainless steel Fitzmill grinder, and the l0 mesh materialwas further ground to l00 mesh in a Model PC 20 Strong-Scott Pulvocrongrinder operated at 3,500 r.p.m. with the classifier at 1,000 r.p.m. andthe tailings return at 100 percent. The resultant powder was remoistenedto l 1.5-] 2.5 percent by weight water in a horizontal ribbon blender,and the moistened material was screened to 40 mesh. The properties ofthe resultant compacted starch powder (starch A,,) are set forth intable 1. Technique 2 (Differential Roll-Milling) The second sample ofthe ground hypochlorite-bleached native cornstarch was compacted, afterbeing moistened to a water content of about 25.2 percent by weight, inan EEMCO Laboratory differential roll mill having l2-in. length rolls of6 in. diameter. The mill was operated with a mill gap of l2 mils, androll speeds of 50 and 70 linear feet/min. on the respective rolls. Rolltemperature was maintained at about 23 C. by cooling water circulatingthrough the rolls. The compacted starch sheet stripped from the rollswas then subjected to three additional passes through the mill. Theresultant compact was then dried to a moisture content of 6-9 percent byweight. The dried compact was ground first to less than about 1.0 mm. ina Wiley mill and then to less than about 0.5 mm. in a Raymond hammermill. The ground material was then remoistened with water to a moisturecontent of ll.8 percent by weight, and screened to mesh. The resultantcompacted starch powder (starch A had the properties set forth in tableI bonlike compact obtained was dried to 7 percent by weight water andthen ground as in technique 2 above. The ground material was thenadjusted to a moisture content of about 12.0 percent by weight, and thenfinally screened to 80 mesh. The properties of the resultant compactedstarch powder (starch The above data indicates that the compacted starchpowders are directly compressible into tablets themselves and thatsuitably hard, nonfriable, rapidly disintegrative tablets containingrelatively high levels of heretofore difiicult-to-tablet drugs, i.e.ascorbic acid, phenacetin, and APAP, advantageously can be preparedusing the compacted starch powders as sole dual-functioningbinder-disintegrant ingredients. Although the NaPAS-containing tabletsdisintegrated relatively slowly, these tablets had suitable hardness andfriability properties; the compacted starches are satisfactory binderseven of this previously difficult-to-tablet drug.

EXAMPLE ll Ac) are Set forth in table in order to compare thebinder-disintegrant properties of TABLE 1 Coldwater Loose Flow- H2Osolu- Swellbulk ability, content, bility, ing density, angle of StarchDescription percent percent; power gun/ml. repose A Hypochloritebleached native corn starch- 10. 0 0. 2-0. 5 1. 9-2. 1 0. 52- 66 44-45 APelletized Starch A 12. 4 .2 6. 6 0. 57 33 ADRM Difierentlal roll-milledstarch A 11.8 13. 1 6. 8 0.60 31 Ans Roll mill compacted starch A 12.011. 6 7. 2 0. 69 31 The data in table 1 indicates that the threedifferent comthe compacted starch powders employed in the presentinvenpaction methods can each produce compacted starch powders,ssentially equivalent in these properties.

Superficially dry tabletting formulations were prepared by thoroughlyblending the resultant compacted starch powders each in turn, withseparate powdered preparations of ascorbic acid, phenacetin, sodiump-amino-salicylate dihydrate (NaPAS) a N-acetyl-p-aminophenol (APAP) inthe proportions set forth below in table 2, incorporating talc and/orcolloidal silica (Cab-o-Sil) as tabletting aids into the formulations,and screening the resultant mixtures to mesh. The 40 free-flowingpowders obtained were then directly tabletted on a Colton No. 204four-punch press manufactured by the Colton Division of Cherry-BurrellCorporation, Detroit, Mich. A set of inch diameter standard cap punchesand dies was employed, and the press was operated at 35 rpm. to producetabletted using the same tabletting procedure. The properties of thetablets obtained also are set forth in table 2.

tion with those of other compacted starches, the starting bleachednative cornstarch (starch A) of example I was converted to a compactedstarch powder using technique 3 of example with the exception that themoisture content of the starting starch was initially adjusted to aboutl8 percent by weight so that the starch was worked and modified to alesser degree. The resultant compacted starch powder was characterizedby a 2.9 percent cold-water solubles content, a swelling power of 3.0, aloose bulk density of 0.49 gm./ml., and flowability corresponding to anangle of repose of more than 40.

The resultant compacted starch powder was tabletted alone using theprocedure of example I. The tablets obtained had an average hardness of3 kg., a friability corresponding to an average weight loss of L93percent, and a disintegration time in water of 0.5-1 .5 minutes. Asevidenced by the poor flowability of the powder and the low hardness andhigh friability of the tablets prepared therefrom, the low cold-watersolubles content powder is not suitable for use as a soledual-functioning binder-disintegrant ingredient in preparing acceptabletablets by direct compression.

TABLE 2 Formulation composition Tablet properties Adiuvants, percent byAverageweight total formulation H20 Fria- Drug/ conbility DisintebiuderColtent, Hardpercent gration Starch weight loidal perness, weight time,

binder Drug ratio 1 Talc silica cent kg. loss minutes Tablet Number:

1 12. 4 13. 7 0. 08 4. 5-5. 0 2 Ascorbic acid.. 7. 3 5. 9 0. 19 1. 5 3Phenacetin.. 8. 4 5. 0 0. 44 2. 5 4 0 7. 4 5. 7 0. 23 1. 5 5 13. 3 6. 40. 39 -80 6 0:100 11. 8 14. 0 0. 12 6. 5-7. 0 7-. Ascorbic 150143..35:65 5. 0 0. 0082 7. 7 4. 5 0. 37 2. 0-2. 5 8 Phenacetin 25:75 0. 00919. 1 5. 4 0. 35 4. 0 9 APAP 25:75 3. 0 0. 0082 8. 4 6. 6 0. 20 2. 5-3. 010 :60 5 0 0.0082 13.3 5. 8 0.51 60-00 11 0:100 12. 0 14. 7 0. 1 9. 0-9.5 12 Ascorbic acid. 30:70 5.0 0. 0092 8. 2 6. 3 0. 16 3. 0 13. APhenacetin 30:70 0. 0091 8. 6 6. 7 0. 42 3. 0-3. 5 14 A AP 30:70 3.00 00093 8.4 7.2 0.43 2.0 15. NaPAS 35:65 3. 5 0 0076 12.7 6. 4 0. 31 -105 1Based on binder dry substance weight.

EXAMPLE m This example illustrates the preparation of suitable tablet.binder-disintegrant starches from oxidized cornstarch and the use ofthe resultant binder-disintegrant starches in the preparation of tabletsby direct compression.

Two samples of ground alkaline hypochlorite-oxidized cornstarch (starchB) were converted to compacted starch powder using techniques 2 and 3 ofexample 1. However, in using technique 2 the feed starch had a moisturecontent of 31.0 percent by weight and the roll temperature wasmaintained at 31 C. and in using technique 3 the feed starch hadmoisture content of 27.1 percent by weight, the roll gap was 0.02 in.,and the force feeder speed was 5 r.p.m. The properties of the resultantcompacted starch powders (starch B and starch B respectively) are setforth in table 3 below. Using the procedure of example 1, tablets wereformed from each of the compacted starch powders alone and formulationsprepared by thoroughly mixing each powder separately with certain drugsand tabletting aids. The compositions of the tablets and theirproperties are shown in table 4 below.

TABLE 3.-STARCH PROPERTIES EXAMPLE V This example illustrates thepreparation of a tablet binderdisintegrant starch from a native highamylose starch and the use of the resultant binder-disintegrant starchin preparing tablets.

The procedure of technique 2 (difierential roll-milling) of example 1was employed to convert a native high amylose starch (commonly known asAmylomaize" and designated starch D) to a compacted starch powder exceptthat a starch feed moisture content of 27.6 percent by weight and rolltem- H1O Cold Flowconwater Loose ability,

tent, solu- Swellbulk angle perbilit ing density, of

Example N 0. Starch Description cent percent power gm./m1. repose BOxidized corn starch 11. 3 1. 3 2. 1

III B RM Differential roll-milled starch B. 11. 7 10. 2 3. 6 34 B50 12.333.6 7.1 27

Iv Native corn star 11. 1 0. 3 1. 9 36 C Differential roll-min ch 0 11.9 6. 9 4. 8 28 V D Native high amylose starch 10. 9 0. 4 2. 6 29 DDRMDifierential roll-milled starch D 11. 9 4. 0 3. 9 31 VI {E Acid-modifiedcorn starch..... 10. 9 1. 1 2. 3 38 Em Difierential roll-milled starch E12.0 17.7 4.0 31 VII F Derivatized corn starch 10. 9 0. 8 2. 1 45 FmmDifierential roll-milled starch F. 12. 1 31. 6. 5 34 VH1 G Gr0ss-linkedstarch 10. 7 1. 9 2. 3 28 GDR Differential roll-milled starch G-.. 11. 921. l 7. 0 29 IX H Native potato starch 13. 9 0. 6 2. 2 31 HDifferential roll-milled starch H.-. 12. 1 21. 0 2. 5 32 EXAMPLE IV Thisexample illustrates the preparation of a suitable tabletbinder-disintegrant starch from native cornstarch and the use 45 of theresultant binder-disintegrant starch in making tablets.

Native cornstarch (starch C) was converted to a compacted perature of 10C. were used. The properties of the starting starch and resultantcompacted starch powder (starch D are set forth in table 3. Theproperties of placebo and drugcontaining tablets prepared using thecompacted starch powder in the general tabletting procedure of example Iare shown in table 4.

TABLE 4 Formulation composition Tablet properties Percent by weighttotal Averageadjuvants,

formula H Fria- Drug conbilit Disinteblnder Coltent, Hardpercent grationTablet Starch wel ht loidal perpass, weight time, Example No. binderDrug rat 0 l Talc silica cent kg loss minute 18 B R 0: 100 11. 7 14. 00.12 6. 5-7. 0 19 Bonn Phenacetin. :60 0.0103 7. 4 5. 4 0. 43 3. 5 20Bmuvr Ascorbic acid- 7. 0 5. 0 0. 16 3. 0 III 21 Bmm NaPAS 12. 8 B. 4 0.34 45-60 22 BnnM APAP 7. 7 7. 8 0. l8 3. 5-4. 0 23 B110 12. 3 10.8 0.0915. 0 24 B10 Phenacetin. 8. 3 4. 6 0. 41 5. 0-6. 0 25 CDB 11.9 14. 3 0.10 5.0-6. 5 26 Conzvr Phenacetin- 7. 7 7. 7 0. 38 3.0-4. 0 IV 27 0mmAscorbic acid- 7. 1 6. 0 0. 31 5. 5-6. 0 28 CDRM N aPAS 13. 3 6. 7 0. 2870-80 29 Goa-M APAP 7. 7 8. 4 0. 14 3. 5-4. 0 30 Dun 11. 9 13. 3 0. 053. 5-4. 0 31 DDnM Phenacetin- 7. 9 7. 1 0. 34 2. 5 32 Dmuvr Ascorbicacid. 6. 4 5. 4 0.31 3. 0-3. 5 33 DDRM N PAS 13. 3 7. 5 0. 28 75-85 34DDRM 7. 7 7. 7 0. 26 2. 0-2. 5 35 Epmvr 12. 0 9. 5 0. 11 4. 0 36 Fnmu12. 1 9. 8 0. 05 9. 5-10. 5 37 GrmM 11. 9 9. 5 0. ll 4. 0 38 Harm 12. 110. 1 0. 12 29. 0

1 Based on binder dry substance weight.

This example illustrates the preparation and use of a tabletbinder-disintegrant starch derived from an acid-modified starch rawmaterial.

An acid-modified starch (starch E) having an alkali fluidity of about 62cc. g. starch, as is basis, 77 F. and 0.375 N sodium hydroxide) wasconverted to a compacted starch powder employing technique 2(differential roll-milling) of example I except that the starch feedmoisture content utilized was 28.0-30.5 by weight, the roll gap was6'mils, and the roll temperature was maintained at 23-26 C. A comparisonof the properties of the starting granular starch and the resultantcompacted starch powder (starch E obtained are set forth in table 3.Following the tabletting procedure of example I, placebo tablets(without drugs) were prepared using the compacted starch powder alone.The properties of the tablets obtained are reflected in table 4.

The results of these tests indicate the resultant compacted starchpowder is a suitable binder-disintegrant ingredient for use in preparingacceptable drug-containing tablets by direct compression as in theprevious examples.

EXAMPLE Vll This example illustrates the preparation an use of a tabletbinder-disintegrant starch obtained from a derivatized granular starchraw material.

A granular derivatized cornstarch containing about 2.5 percent acetylgroups (starch F) was converted to a compacted starch powder usingtechnique 2 (differential roll-milling) of example 1 except that thefeed starch moisture content was 28.3-3l percent by weight, a roll gapof 12 mils was employed, and roll temperatures were maintained at 23-24C. The properties of the starting starch and the resultant compactedstarch powder (starch F are set forth in table 3. Using the tablettingprocedure of example I, placebo (drugfree) tablets were prepared fromthe compacted starch powders. The properties of the tablets are shown intable 4.

When substituted as the binder-disintegrant ingredient in thepreparation of the drug-containing tablets described in the precedingexamples, the compacted starch powder provides tablets of propertiescomparable to those mentioned.

EXAMPLE Vlll This example illustrates the preparation and use of atablet binder-disintegrant starch obtained from a cross-linked granularstarch raw material.

The procedure of example VI was repeated with the exception ofsubstituting a granular cross-linked cornstarch obtained by reactingoxidized cornstarch with phosphorus oxychloride (starch G) for theacid-modified starch. The properties of the starting starch andresultant compacted starch powder (starch G are set forth in table 3.The characteristics of the tablets obtained are shown in table 4.Drugcontaining tablets prepared by direct compression, using theresultant compacted starch powder as a binder-disintegrant ingredient asin the preceding examples, have characteristics similar to such tabletsdescribed above.

EXAMPLE IX This example illustrates the preparation and utilization of atablet binder-disintegrant starch derived from potato starch.

The procedure of example Vll was repeated except that native potatostarch (starch H) was substituted for the derivatized cornstarch. Acomparison of the properties of the starting starch and the resultantcompacted starch powder (starch H is shown in table 3, and thecharacteristics of the placebo tablets prepared therefrom are listed intable 4. When employed as a binder-disintegrant ingredient in preparingdrug-containing compressed tablets, such as those prepared above bydirect compression, the resultant compacted starch powder providesacceptable tablets.

EXAMPLE x This example illustrates an embodiment of the presentinvention wherein a binder-disintegrant starch is employed incombination with an uncompacted starch in the preparation of activeingredient tablets by direct compression, the uncompacted starch beingemployed as a filler and disintegrant ingredient in the tablets.

A sample of starch D (differential roll-milled native cornstarch)described above in example iv was thoroughly mixed with sodiump-aminosalicylate dihydrate (NaPAS) and ground bleached nativecornstarch containing about 10 percent by weight moisture in a weightratio of drug:compacted starchzuncompacted starch of 30:60:10, starchdry substance basis. Talc and colloidal silica (Cab-o-Sil) also wereadded during the mixing in amounts of 6.0 percent and 0.0l09 percent byweight of the total fonnulation, respectively. The resultant powderwhich had a moisture content of 12.1 percent by weight was tabletteddirectly using the procedure of example I. The resultant tablets werecharacterized by an average hardness of 8.7 kg., a friabilitycorresponding to an average weight loss of 0.24 percent, and adisintegration time of 20-26 minutes.

EXAMPLE Xl This example illustrates embodiments of the present inventionwherein a binder-disintegrant starch is employed in the preparation oftablets by direct compression wherein the tablets are intended fornonpharmaceutical uses.

Using starch A, (pelletized bleached native cornstarch) described inexample I as the binder-disintegrant ingredient and the tablettingprocedure of example 1, tablets that disintegrate rapidly in water andhave excellent hardness and friability properties are prepared from thefollowing formulations:

Plant Root-growth Stimulant Tablets Parts by weight Starch A,

l-Naphthalene acetic acid 9 Colloidal silica (Cab-o-Sil) 1 GarlicTablets Starch A, 23

Powdered garlic (Dehydrated) 7U Colloidal silica (Cah-n-Sil) 2 Table 5below contains comparative data showing that compaction of starch so asto impart the properties set forth above in table form on page 7 rendersthe starch powder useful in forming tablets by direct compressionwhereas the same starch, noncompacted, does not have this property. Inthe table the heading Allis-Chalmers Compacter Conditions" refers totechnique 3 set forth on page 22 above while the heading DifferentialRoll Mill Conditons refers to technique 2 set forth above on pages 21and 22. The starch used in samples Nos. 1-10, 12 and 13 is ordinarypowder native cornstarch bleached with sodium hypochlorite to make itwhiter while the oxidized starch used in sample 1 l is a corn starchoxidized by sodium hypochlorite under alkaline conditions until it hasabout 0.5 percent carboxyl groups.

The data in table 5 may be summarized as follows:

a. Sample 1, 2, 7, 8, 9 and 10, which were not compacted and which didnot fall within the parameters set forth on page 7 with respect to atleast two of cold-water solubility, swelling power, loose bulk density,and moisture content, could not be tabletted.

b. Samples 3, 4, 5, 6, ll, l2 and I3, which were compacted, could betabletted. However, sample 3 had a cold-water solubility below therequired minimum and the tablets formed therefrom were not satisfactorysince they were not suffrciently hard and were excessively friable.Samples 4, 5 and 6 had values for cold-water solubility, loose bulkdensity and swelling power within the range as set forth in the table onpage 7.

c. Sample 13, which was compacted well beyond any of the others, hadexcess cold-water solubility and excess swelling cent of said powder is-80 mesh size, at least about percent of said powder is +270 mesh size,and from about to about 90 percent of said powder is -270 mesh size saidpowder being adapted to function as the essential, bifunctionaldisinower. While it could be tabletted, the bl t did not di i 5 tegrantand binder in the direct compression method of tablet tegrate in overminutes, well beyond the requirements for a ma yf q m useful tabletbinder-disintegrant. 2. The compressed tablet according to claim 1wherein said d. In the Allis-Chalmers Compacter, increasing compactionactive ingredient is a pharmaceutically active compound. is obtained bynarrowing the gap, increasing the water con- 3. The compressed tabletaccording to claim I wherein said tent, increasing the speed of thefeeder, increasing the bearing 10 active ingredient is anonphannaceutically active conmound. pressure or any combination ofthese. The data for samples 3, 4. The compressed tablet according toclaim 1 wherein said 4, 5 and 6 show that increasing the extent ofcompaction incompacted starch powder constitutes at least aboutpercreased the tablet hardness and disintegration time while cent of thetotal weight amount of binder in said tablet. decreasing friability. 5.The compressed tablet according to claim 1 wherein the TABLE 5- AllisChalmers eompacter Powder subjected to tabletting conditions 80 mesh)Tablet H10 Bearing Percent Loose Friabllity in Roll Force prescold bulkSwell- Per- Hardpercent Disintefeed gap, feeder, sure, water density ingcent ness weight gratlon, Type of starch starch inches r.p.m lbs.solubles gm./ml. power H1O (kg.) loss minutes Sample Number:

i313"'""""ijfifiiiiif'iiiifIi: $819 ::133::::::::::::::::::::::::: 3333:25 2. 1? 32? Unable to make tablets 18.2 2. 0 0. 49 2. 97 11. 0 3.0 1.93 0. 5-1. 5 18. 2 7.4 0. 50 5.02 11.9 7.3 0. 32 5.0-5. 5 21.6 11. 60.59 7.17 11.9 14. 7 0.10 9.0-9.5 21.6 13. 3 0. 9. 04 11.9 12.2 0. 0518.0-19.5 11.6 0.4 0.51 2.01 11.6 13:1 8:3 8: i3 '1??? 13:1 Unable tomake tables Difierential roll mill conditions Roll Rgsll Noi gap spee omils fin/min: passes 11 Oxidized starch- 31. 0 12 50-70 2 10. 2 0. 56 3.64 11. 7 14. 0 0. l2 6. 5-7. 0 12.. 25. 2 12 50-70 4 13. 1 0. 6. 79 11.8 13. 2 0. 13 7. 5-8. 5 13 27.0 12 50-70 4 61.1 0. 56 12. 3 11.8 14. s0. 01 2 4 1 Minutes eqsulvalent to 128 to 180 passes. 2 Had not dintegrated in 45 minutes when test was halted.

We claim:

1. A directly compressed tablet requiring a disintegrant and a binder,having resistance to breaking and crumbling, and being capable ofdisintegrating in an a ueous medium, said tablet comprising (a) anactive ingredten by which said tablet derives its utility and (b) apulverulent cohesive binder for said active ingredient, said bindercomprising as the only dualfunction binder and tablet-disintegrant adirectly compressible compacted starch powder in a concentration thatprovides substantial binding action and substantially acceleratesdisintegration of said tablet in an aqueous medium, said compactedstarch powder being a superficially dry, free-flowing material in whichthe starch is in the form of a mixture of birefringent granules andnonbirefringent fragments of granules, in which some aggregates ofgranules and fragments are present and having a cold-water solubility inthe range of from about 4 to about 40 percent by weight, dry substancebasis, a swelling power in the range of from about 2.5 to about l2, aloose bulk density in the range of from about 0.50 to about 0.70 gramper milliliter, a moisture content in the range of from about 9 to about16 percent, total weight basis, and a particle size distribution suchthat said powder is essentially free of +40 mesh size material and thaton a total weight basis, at least 90 peramount of said active ingredientin said tablet is in the range of from about 5 percent to about percentdry substance weight basis.

6. The compressed tablet according to claim 1 wherein said compactedstarch powder constitutes at least about 50 percent of the total weightamount of binder in said tablet, has a cold-water solubility in therange of from about 6 to about 20 percent, dry substance weight basis,and a swelling power in the range of from about 3.5 to about 10, andcontains, on a total weight basis, from about 45 to about 75 percent ofmaterial which is -270 mesh.

7. The compressed tablet according to claim 6 wherein said compactedstarch is a compacted granular cornstarch raw material.

8. The compressed tablet according to claim 7 wherein said granularcornstarch raw material is bleached native cornstarch and said compactedstarch powder has a cold-water solubility in the range of from about 6to about 15 percent, dry substance weight basis, and a swelling power inthe range of from about 5 to about 8.

i i Q i i UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PatentNo. 3,622,677 Dated November 23, 1971 Inventor(s) Rolland W. P. Shortand Frank Verbanac It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 3, line 41, "powers" should be --powders--.

Column 9, line 17, "formations" should be --formula.tions-.

Column 11, line 36, "a" should be -a.nd--.

Column ll, Table 2, last column, next to last entry reading as "2.0should be --2.5-- and last entry reading as "90-105" should be--90-lOO--.

Column 13, Table 3, third column, line 5, "roll-minded" should be-rollmilled-.

Column 15, line 7, should be --gm.--

Column 15, line 26, "an" should be --a.nd-.

Column 16, line 57, "Conditons" should be "Conditions".

Signed and sealed this 9th day of January 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents

2. The compressed tablet according to claim 1 wherein said activeingredient is a pharmaceutically active compound.
 3. The compressedtablet according to claim 1 wherein said active ingredient is anonpharmaceutically active compound.
 4. The compressed tablet accordingto claim 1 wherein said compacted starch powder constitutes at leastabout 50 percent of the total weight amount of binder in said tablet. 5.The compressed tablet according to claim 1 wherein the amount of saidactive ingredient in said tablet is in the range of from about 5 percentto about 90 percent dry substance weight basis.
 6. The compressed tabletaccording to claim 1 wherein said compacted starch powder constitutes atleast about 50 percent of the total weight amount of binder in saidtablet, has a cold-water solubility in the range of from about 6 toabout 20 percent, dry substance weight basis, and a swelling power inthe range of from about 3.5 to about 10, and contains, on a total weightbasis, from about 45 to about 75 percent of material which is -270 mesh.7. The compressed tablet according to claim 6 wherein said compactedstarch is a compacted granular cornstarch raw material.
 8. Thecompressed tablet according to claim 7 wherein said granular cornstarchraw material is bleached native cornstarch and said compacted starchpowder has a cold-water solubility in the range of from about 6 to about15 percent, dry substance weight basis, and a swelling power in therange of from about 5 to about 8.